The intracellular aggregation of hyperphosphorylated tau in neurofibrillary tangles (NFTs) is a neuropathological hallmark of Alzheimer's Disease (AD). While tau pathology is correlated with both synaptic loss and neurodegeneration in AD, implicating a major role for tau accumulation in cognitive decline, the mechanisms of tau aggregation and cell toxicity remain unknown. We propose to provide novel insight into the extent to which abnormalities in nuclear pore complexes (NPCs) and the resulting nucleocytoplasmic transport (NCT) defects contribute to AD pathogenesis. NPCs are complex, molecular assemblies consisting of multiple copies of proteins called nucleoporins (Nups) that regulate the macromolecular trafficking of protein and RNA between the nucleus and cytoplasm. Previous reports have identified nuclear membrane irregularities that often associate with NFTs. However, the pathophysiology of tau and its relationship to nuclear function/integrity is not well understood. We have amassed a series of preliminary data demonstrating that disruptions of the NPC and functional nuclear transport are present in cells containing hyperphosphorylated tau in human AD brain, as well as in mouse and cellular models of tauopathy. Given the extent of NPC and NCT dysfunction in ALS and HD, our preliminary studies in AD/FTLD-tau suggest that impaired NPC function may represent a common mechanism of neurodegeneration. Specifically in AD, we find that a major nuclear pore component, Nup98, is mislocalized from the nuclear membrane and co-aggregates with tau in both human brain and transgenic tau mouse models. Tau and Nup98 directly interact and we have discovered that Nup98 can potently promote tau filament formation in vitro. Based on these key findings, we will test the overall hypothesis that tau-Nup98 interactions underlie a pathologically important disruption of nuclear pore function and represent a key mediator of neurotoxicity in AD and related tauopathies. As the ultimate goal of our project is to develop a disease- modifying therapeutic strategy, we will assess whether either clearing tau/Nup98 inclusions or rescuing the NCT defects are necessary and/or sufficient to ameliorate tau toxicity. Our studies specifically will: 1) Investigate alterations in nuclear pore complexes in human AD/FTD and model systems. These studies will establish NPC defects as a novel, pathological feature of tauopathy; 2) Determine the functional alterations in nucleocytoplasmic transport resulting from nuclear pore abnormalities in AD/FTD. These studies will determine if aberrant functional NCT is characteristic of cells containing tau lesions.; and finally, 3) Examine whether disaggregases rescue NPC/NCT pathway defects in vivo. These studies will help to test the hypothesis that NPC defects can contribute to tau toxicity